Inter-phenylene-13,14-dihydro-PG amides

ABSTRACT

The present invention relates to inter-phenylene-13,14-dihydro-PG amides. These compounds are pharmacological agents, being prolonged orally active platelet aggregation inhibitors in mammalian species. These compounds are accordingly useful for antithrombotic applications.

This application is a continuation-in-part of Ser. No. 788,455, filed Apr. 18, 1977, now U.S. Pat. No. 4,100,192, issued July 11, 1978.

SPECIFICATION

The present invention relates to inter-phenylene-13,14-dihydro-PG amides, the essential material constituting a disclosure of which is incorporated here by reference from Ser. No. 788,455. In particular, the present invention relates to inter-phenylene-13,14-dihydro-PG amides of the unsubstituted inter-phenylene PG amides described in Ser. No. 788,455 now U.S. Pat. No. 4,100,192. 

I claim:
 1. A prostaglandin analog of the formula ##STR1## wherein D is ##STR2## wherein R₈ is hydrogen or hydroxy; wherein g is one, 2, or 3;wherein Z₃ is oxa or methylene; wherein L₁ is ##STR3## or a mixture of ##STR4## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is methyl only when the other is hydrogen or methyl; wherein M₁ is ##STR5## wherein R₅ is hydrogen or methyl; wherein m is one to 5, inclusive; and wherein R₂₁ and R₂₂ are(i) hydrogen; (ii) alkyl of one to 12 carbon atoms, inclusive; (iii) cycloalkyl of 3 to 10 carbon atoms, inclusive; (iv) aralkyl of 7 to 12 carbon atoms, inclusive; (v) phenyl; (vi) phenyl substituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy or nitro; (vii) hydroxylalkyl of one to 4 carbon atoms, inclusive; (viii) dihydroxyalkyl of one to 4 carbon atoms; or (ix) trihydroxyalkyl of one to 4 carbon atoms;with the further proviso that not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl.
 2. A prostaglandin analog according to claim 1, wherein D is ##STR6##
 3. A prostaglandin analog according to claim 2, wherein R₈ is hydrogen.
 4. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-11-deoxy-PGF.sub.1, amide, a prostaglandin analog according to claim
 3. 5. A prostaglandin analog according to claim 2, wherein R₈ is hydroxy.
 6. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-11-deoxy-PGF.sub.1, amide, a prostaglandin analog according to claim
 5. 7. A prostaglandin analog according to claim 1, wherein D is ##STR7##
 8. A prostaglandin analog according to claim 7, wherein R₈ is hydrogen.
 9. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-9-deoxy-PGD₁, amide, a prostaglandin analog according to claim
 8. 10. A prostaglandin analog according to claim 7, wherein R₈ is hydroxy.
 11. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGD₁, amide, a prostaglandin analog according to claim
 10. 12. A prostaglandin analog according to claim 1, wherein D is ##STR8##
 13. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-9-deoxy-9,10-didehydro-PGD₁, amide, a prostaglandin analog according to claim
 12. 14. A prostaglandin analog according to claim 1, wherein D is ##STR9##
 15. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGA₁, amide, a prostaglandin analog according to claim
 14. 16. A prostaglandin analog according to claim 1, wherein D is ##STR10##
 17. A prostaglandin analog according to claim 16, wherein R₈ is hydrogen.
 18. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-11-deoxy-PGE₁, amide, a prostaglandin analog according to claim
 17. 19. A prostaglandin analog according to claim 16, wherein R₈ is hydroxy.
 20. A prostaglandin analog according to claim 19, wherein Z₃ is methylene.
 21. A prostaglandin analog according to claim 20, wherein Z₃ is attached to the phenyl ring in the position meta to methylene.
 22. 3,7-inter-m-Phenylene-4,5,6-trinor-13,14-dihydro-PGE₁, amide, a prostaglandin analog according to claim
 21. 23. A prostaglandin analog according to claim 19, wherein Z₃ is oxa.
 24. A prostaglandin analog according to claim 23, wherein M₁ is ##STR11##
 25. 15-epi-3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE₁, amide, a prostaglandin analog according to claim
 24. 26. A prostaglandin analog according to claim 23, wherein M₁ is ##STR12##
 27. A prostaglandin analog according to claim 26, wherein Z₃ is attached to the phenyl ring in the position meta to methylene.
 28. A prostaglandin analog according to claim 27, wherein m is
 3. 29. A prostaglandin analog according to claim 28, wherein g is
 3. 30. 2a,2b-Dihomo-3,7-inter-m-phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE₁, amide, a prostaglandin analog according to claim
 29. 31. A prostaglandin analog according to claim 28, wherein g is one.
 32. A prostaglandin analog according to claim 31, wherein at least one of R₃ and R₄ is methyl.
 33. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-16,16-dimethyl-13,14-dihydro-PGE₁, amide, a prostaglandin analog according to claim
 32. 34. A prostaglandin analog according to claim 31, wherein at least one of R₃ and R₄ is fluoro.
 35. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-16,16-difluoro-13,14-dihydro-PGE₁, amide, a prostaglandin analog according to claim
 34. 36. A prostaglandin analog according to claim 31, wherein R₃ and R₄ are both hydrogen.
 37. A prostaglandin analog according to claim 36, wherein R₅ is methyl.
 38. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-15-methyl-13,14-dihydro-PGE.sub.1, amide, a prostaglandin analog according to claim
 37. 39. A prostaglandin analog according to claim 36, wherein R₅ is hydrogen.
 40. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE₁, n-propylamide, a prostaglandin analog according to claim
 39. 41. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE₁, ethylamide, a prostaglandin analog according to claim
 39. 42. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE₁, methylamide, a prostaglandin analog according to claim
 39. 43. 3,7-inter-m-Phenylene-3-oxa-4,5,6-trinor-13,14-dihydro-PGE₁, amide, a prostaglandin analog according to claim
 39. 